Preparation of small crystals

ABSTRACT

Small crystals are made by mixing a solution of a desired substance with an anti-solvent in a fluidic vortex mixer in which the residence time is less than 1s, for example 10 ms. The liquid within the fluidic vortex mixer ( 12 ) is subjected to high intensity ultrasound from a transducer ( 20, 22 ). The solution very rapidly becomes supersaturated, and the ultrasound can induce a very large number of nuclei for crystal growth. Small crystals, for example less than 5 μm, are formed. The resulting suspension is treated so as to add or remove ingredients, and then spray dried using an atomizer tuned to create small droplets in such a way that each droplet should contain not more than one crystal. Crystal agglomeration is hence prevented.

This invention relates to an apparatus and a process for preparing smallcrystals of size less than 10 μm.

The control of crystal and precipitate particle size and morphology isvery important in some circumstances, in particular in thepharmaceutical and agro-chemical industries in which the final productform is a fine powder. The way in which an active ingredient behaves,whether in the body or upon the surface of a leaf for example, dependscritically upon the particle size of the product, and the particularcrystal form. Small particles may be made by processes such as milling,but such processes may have a detrimental effect on the materialproperties and may also produce a significant proportion of particleswhich are too small for the desired use, so that crystallisation ofcrystals in the desired size range directly from a solution would bedesirable.

For many years it has been known to bring about crystallisation bymixing a solvent containing a product to be crystallised with ananti-solvent, so that after mixing the solution is supersaturated andcrystallisation occurs. GB 2 341 120 A describes a system in which themixing utilizes a fluidic vortex mixer, and in which the emergingmixture is supplied directly to a precipitate entrapment device. Theterm anti-solvent means a fluid which promotes precipitation from thesolvent of the product (or of a precursor for the product). Theanti-solvent may comprise a cold gas, or a fluid which promotes theprecipitation via a chemical reaction, or which decreases the solubilityof the product in the solvent; it may be the same liquid as the solventbut at a different temperature, or it may be a different liquid from thesolvent. EP 0 449 454 A (=GB 2 242 376) describes a system for bringingabout on-line precipitation in which liquid reagents are thoroughlymixed using a fluidic vortex mixer, the mixture then being passedthrough a vessel comprising linked vortex cells in which a pulsed flowensures a well-defined residence time, hence ensuring particles of aselected mean size are created. The benefits of applying intenseultrasound during a crystallisation process have also been recognized,for example as described in an article by Chris Price in PharmaceuticalTechnology Europe, October 1997, as such insonation can be used toinitiate nucleation, so overcoming the problems that can arise fromsupersaturation.

WO 02/089942 describes a method of performing crystallisation in which asaturated solution is mixed with an anti-solvent by passage through afluidic vortex mixer, in which the liquid within the fluidic vortexmixer is subjected to high intensity ultrasound. A fluidic vortex mixercomprises a vortex chamber with two or more peripheral inlets, at leastone of which is substantially tangential, and with an axial outlet. Sucha device can achieve very rapid and thorough mixing in a very shortspace of time; for example the residence time in the mixer may be lessthan 0.5 s, or even less than 0.1 s, for example 20 ms or 10 ms, thoughusually at least 1 ms. The chamber is substantially cylindrical, andcontains no baffles to disrupt the vortex flow. Such a fluidic mixer cantherefore achieve a very high degree of supersaturation, because of therapid and very thorough mixing with the anti-solvent. This process canenable crystals of a material to be formed which are less than 10 μm insize, for example less than 5 μm or less than 1 μm. Such small crystalsmay be of a suitable size for use in inhalers.

Although such a process enables you to make small crystals of awell-defined size, drying the crystals to remove all the liquidassociated with them and so to prepare a free-flowing powder is notstraightforward. Agglomeration of the crystals must be prevented.Furthermore the liquid phase may contain other solutes in solution, andthe crystals must be separated from these solutes before drying.Conversely, it may be desirable to add other ingredients before dryingthe crystals. Filtration or centrifuging, followed by oven or drumdrying, which is known for use with larger crystals, is inappropriatewith such small crystals as the filtration rate would be very slow andthe crystals will tend to form a cake or large agglomerates in thedryer. The use of spray drying to dry crystals has been suggested forexample in EP 1 048 668 (for riboflavir . . . ), and is also suggestedin EP 976 750 (for Z-valacyclovir), but the problem of preventingaggregation or agglomeration has not been considered.

According to the present invention there is provided a method forpreparing dry crystals from a suspension of crystals in a liquid, thecrystals being of a well-defined size that is in the range 1 μm to 10μm, the method comprising spray drying the suspension using an atomisertuned to create small droplets in such a way that each droplet shouldcontain not more than one crystal.

The atomiser may for example be a pneumatic, rotary orultrasonic/piezoelectric atomiser. If the droplets are sufficientlysmall and/or the suspension sufficiently dilute, then the small dropletsare very unlikely to contain more than one crystal, so that the dryingprocess generates single unagglomerated crystals. Hence the method maycomprise treating the suspension so as to add or remove ingredients ordilute the suspension, prior to the spray-drying step. Many of thedroplets will in fact contain no crystals at all, and therefore willevaporate completely. Typically the diameter of the droplets might beabout two or three times the crystal size. If the droplets are more thanabout twice the crystal size there is a risk that some droplets maycontain more than one crystal, but this risk can be significantlyreduced by diluting the suspension before the drying process, forexample with antisolvent.

The present invention also provides a method of preparing dry crystalsfrom a saturated solution, in which the saturated solution is mixed withan anti-solvent by passage through a fluidic vortex mixer, the liquidwithin the fluidic vortex mixer being subjected to high intensityultrasound to initiate crystallisation and so to form a suspension ofcrystals of a well-defined size that is in the range 1 μm to 10 μm,treating the suspension so as to add or remove ingredients or dilute thesuspension, and then spray drying the suspension using an atomiser tunedto create small droplets in such a way that each droplet should containnot more than one crystal.

Drying in the manner described above overcomes the problem ofagglomeration. Hence the resulting crystals will be free-flowing and ofa narrow size distribution.

Prior to spray drying it may be desirable to add other ingredients, andthese may be crystalline or may be in solution. Hence the method mayinvolve the step of mixing the suspension of crystals with such otheringredients prior to the spray drying. An ingredient added as a solutionmay then be adsorbed onto the surface of the crystals, so that theresulting dry crystals are coated with that ingredient. As intimatedabove it may also be desirable to add additional liquid to thesuspension to lower the concentration and so reduce the risk of twocrystals being present in a droplet.

Such mixing may be carried out in a batch mixing tank, or with a fluidicvortex mixer.

Furthermore, prior to spray drying it may be necessary to remove othersolutes from the suspension. This would be particularly the case if thecrystals had been generated by reaction crystallisation. Some form ofsolid-liquid separation and washing is clearly required before spraydrying, but the very small crystal size makes separation and washing ona filter or centrifuge extremely slow. Preferably the suspension ispassed through a train of two or more hydrocyclones in counter-currentto a wash liquid. The wash liquid may be the antisolvent, or anotherliquid in which the crystals are insoluble. Alternatively the suspensionmay be diluted with a wash liquid, and then subjected to cross-flowfiltration using a microfilter or ultrafilter to remove the excessliquid. If the crystal size is greater than about 2 μm then the use ofhydrocyclones is satisfactory, but for crystal sizes less than about 2μm the use of cross-flow filtration may be necessary as it is difficultto operate a hydrocyclone with a sufficiently small cut-off size.

The invention also provides apparatus for performing the said methods.

The invention will now be further and more particularly described, byway of example only, and with reference to the accompanying drawings, inwhich:

FIG. 1 shows a longitudinal sectional view of a crystallisationapparatus incorporating a fluidic mixer;

FIG. 2 shows a transverse sectional view on the line 2-2 of FIG. 1;

FIG. 3 shows particle size distributions for crystals made in twodifferent ways;

FIG. 4 a shows a diagrammatic flow path of a crystal preparationapparatus incorporating the fluidic mixer of FIG. 1, in which otheringredients or diluent are added;

FIG. 4 b shows an alternative to the apparatus of FIG. 4 a;

FIG. 5 shows a diagrammatic flow path of another crystal preparationapparatus incorporating the fluidic mixer of FIG. 1, in which crystalsare washed before drying; and

FIGS. 6 a and 6 b show alternatives to the apparatus of FIG. 5.

Referring now to FIG. 1, a crystallisation apparatus 10 comprises avortex mixer 12 including a cylindrical chamber 14 of diameter 15 mmwith an axial outlet 16 at the centre of an end wall, and with fourtangential inlets 18 (only two of which are shown in FIG. 1) around itsperiphery. A saturated solution S of a desired substance is supplied totwo inlets 18, and an anti-solvent A is supplied to the alternate twoinlets, as indicated in FIG. 2. An ultrasonic probe 20 is mounted at thecentre of the other end wall and projects into the middle of the chamber14, its other end being connected to a 300 kHz transducer 22. The outlet16 communicates with a product receiver vessel 24, an array of 20 kHzultrasonic transducers 26 being mounted on the outside of the wall ofthe vessel 24.

Thus in use of the apparatus 10, the saturated solution S is thoroughlyand rapidly mixed with the anti-solvent A, the volume of the chamber 14and the flow rates being such that the residence time in the chamber 14is for example 10 ms. The ultrasonic energy from the probe 20 insonatesthe entire volume of the chamber 14 with sufficient intensity to causenucleation, as localized cavitation occurring on a microscopic scalepromotes changes in fluid temperature and pressure that inducenucleation (and also promotes formation of the most stable polymorph).By adjusting the power of the ultrasound, and the residence time in thechamber 14, the degree of nucleation can therefore be controlled. Theultrasound has the additional benefit that any crystal deposits withinthe chamber 14 tend to be removed from the surfaces. Within the receivervessel 24 the crystal growth process is completed, the ultrasound fromthe transducers 26 breaking up any crystal agglomerations and preventingsurface fouling.

It will be appreciated that the solvent in the solution S and theanti-solvent A must be selected as suitable for a particular substance.Preferably they are miscible with each other. As examples, in some casesthe solvent might be acetone, and the anti-solvent be water; or thesolvent might be methanol and the anti-solvent be water; or the solventmight be dimethyl formamide and the anti-solvent be water. The selectionof appropriate solvent and anti-solvents must be made in accordance withthe substance to be crystallised.

It will also be appreciated that the ultrasound may be transmitted intoa fluidic vortex chamber in which mixing is occurring in a differentway, for example an ultrasonic transducer may be coupled to the end wallof the chamber. This is particularly applicable with a vortex chamber ofdiameter above say 20 mm, for example with a chamber of internaldiameter 50 mm. Furthermore, if the crystal growth process is slow theoutlet from the vessel 24 or from the fluidic mixer 14 may be suppliedto a pulsed flow reactor comprising linked vortex cells in which apulsed flow ensures a well-defined residence time, as described in GB 2242 376 B or as described in WO 00/29545; as in the holding vessel 24,each vortex cell in such a pulsed flow reactor may be supplied withwall-mounted transducers to suppress agglomeration and prevent fouling.Such transducers may be energized continuously to encourage formation ofsmall crystals.

In the apparatus of FIG. 1 the mixture of liquids and crystals generatedin the fluidic vortex mixer 12 is fed into a receiver vessel 24 in whichthe crystal growth process is completed. The crystals initially formedin the mixture are small, and have a narrow size distribution. Crystalripening may occur in the receiver vessel 24, with the larger crystalsgrowing at the expense of the smaller crystals, which re-dissolve. Ifcrystal ripening is not desirable, it may be preferable to omit thereceiver vessel 24, and proceed directly to the formation of liquiddroplets in a spray dryer, as discussed below, but in many cases anysuch crystal ripening is advantageous.

Referring now to FIG. 3, the crystal size distribution (marked F) isshown for crystals of a pharmaceutical product driven out of solution byan anti-solvent (drowning out crystallisation), using such a fluidicvortex mixer 12. For comparison, the size distribution obtained with astirred tank reactor is also shown, marked T. In the case of the fluidicmixer, crystals were trapped onto a filter paper using a vacuum pumpfrom the spray emerging from the vortex mixer 12, to provide a sample.It will be observed that the fluidic vortex mixer gives a very narrowsize distribution (about 3.0-4.5 μm), whereas the stirred tank gives afar broader size spectrum (about 3 μm to 30 μm).

Referring now to FIG. 4 a, a crystal preparation apparatus 30 is shown,incorporating a fluidic mixer 12 with an ultrasonic transducer 22 asshown in FIG. 1. The outlet from the fluidic mixer 12 is fed into abatch mixing tank 32 provided with ultrasonic transducers 34 coupled tothe walls to suppress any agglomeration. Other ingredients are addedinto the tank 32 through an inlet duct 36. This could be for example anexcipient, which, if it is itself crystalline, could have been producedin a second fluidic mixer 12 with an ultrasonic transducer 22 (notshown). Alternatively it might be a solution of a coating material whichit is desired to absorb onto the surfaces of the crystals before theyare dried. The output from the batch mixing tank 32 is pumped by a pump38 into a spray dryer 40 which uses a pneumatic atomiser tuned to givedroplet diameters not more than three times the size of the crystals.The droplets are therefore unlikely to contain more than one crystal,and will therefore dry as a single unagglomerated crystal. The outputfrom the spray dryer 40 is therefore a free-flowing powder consistingalmost exclusively of single crystals along with the coating material(or the excipient).

If the concentration of crystals in the batch mixing tank 32 is so highthat there is a significant probability of two crystals being present ina droplet, the atomiser may be tuned to produce smaller droplets, oralternatively additional non-solvent liquid may be added through theduct 36 to reduce the crystal concentration.

The pneumatic atomiser is tuned by adjusting the nozzle size and/or theratio of air to liquid fed to it. The larger the proportion of atomizingair, the smaller is the mean diameter of the droplets.

Referring now to FIG. 4 b, in an alternative crystal preparationapparatus 50 the outlet from the ultrasonically irradiated fluidic mixer12 is supplied to one inlet of a second vortex mixer 52, and the otheringredient or ingredients are supplied to another inlet of the vortexmixer 52 through a duct 54. The mixture emerging from the outlet of thesecond vortex mixer 52 is supplied directly (or via a pump) to a spraydryer 40. The apparatus 50 operates in substantially the same way as theapparatus 30, but can operate continuously rather than treating a batch.

Referring now to FIG. 5, there is shown a flow diagram for a crystalpreparation apparatus 60 for use in a context in which the liquidemerging from the ultrasonically irradiated fluidic mixer 12 containssolutes which are not required in the dried product. The outlet from thefluidic mixer 12 is fed into a tangential inlet of a hydrocyclone 62.The crystals emerge through the bottom of the hydrocyclone 62 (duct 63),and are fed into the tangential inlet of a second hydrocyclone 64. Thecrystals emerge again from the bottom (duct 65), and are then fed intothe spray dryer 40. Washing liquor 66 flows through the hydrocyclones 64and 62 in countercurrent to the crystals, the fresh liquor 66 beingsupplied to the tangential inlet of the second hydrocyclone 64, theliquid phase emerging from the top of the hydrocyclone 64 (duct 67) tobe fed into the tangential inlet of the first hydrocyclone 62, and spentwashing liquor emerges from the top of the hydrocyclone 62 (duct 68).

The hydrocyclones 62 and 64 are preferably of small diameter, forexample of diameter in the range 10-25 mm, as such narrow hydrocyclonescan operate with particle cut diameters less than 4 μm, for example aslow as 2 μm. Suitable hydrocyclones are available from Axsia Mozley Ltd,Redruth, Cornwall. The hydrocyclones must be arranged to operate so thattheir particle cut size is just larger than the size of the crystals, toprovide good separation between the crystals and the liquids. It will beappreciated that there might instead be a larger number of hydrocyclonesin series, for example three or even four. In each case fresh washingliquor must be supplied to an inlet of the last hydrocyclone in theseries, and spent washing liquor be removed from the top outlet of thefirst hydrocyclone.

Referring now to FIG. 6 a there is shown an alternative crystalpreparation apparatus 70 is shown in which the liquid emerging from thefluidic mixer 12 again contains solutes which are to be removed beforefurther processing of the crystals. In this case the process operates ina batch mode. The outlet from the fluidic mixer 12 is fed into atangential inlet of a hydrocyclone 62. The crystals emerge from thebottom (duct 63) and are fed into a first batch mixing tank 72 to whichfresh wash liquor is supplied through a duct 73; the spent washingliquor emerges from the top of the hydrocyclone 62 (duct 68). Inoperation the mixing tank 72 may initially be full of fresh wash liquor,and in the first stage the crystals gradually flow into the first mixingtank 72, as spent washing liquor emerges from duct 68 (to drain). As asecond stage, flow through the fluidic mixer 12 is stopped (valve 75),and instead the suspension in the first mixing tank 72 is pumped by apump 74 through the hydrocyclone 62 into a second mixing tank 76containing fresh washing liquor. Thus during the second stage thesuspension of crystals gradually flows into the second mixing tank 76,and spent washing liquor emerges from duct 68. As a third stage, thesuspension of crystals may be pumped through the hydrocyclone 62 back tothe first mixing tank 72, after first refilling the tank 72 with freshwash liquor. Stages two and three can be repeated as many times as arenecessary to achieve the desired degree of washing.

When the crystals have been adequately separated from the liquidcontaminants, any desired additional ingredients can be added to thesuspension in whichever mixing tank 72 or 76 is appropriate. Thesuspension can then be pumped by pump 78 to the spray dryer 40.

Alternatively, in place of the hydrocyclones 62 or 64, the liquid mightbe separated from the crystals in the washing process using a crossflowfilter, either a microfilter or an ultrafilter. This is preferable wherethe crystals are smaller than about 2 μm, and may also be used withlarger crystals. Referring to FIG. 6 b, an alternative crystalpreparation apparatus 80 is shown in which the liquid emerging from thefluidic mixer 12 again contains solutes which are to be removed beforefurther processing of the crystals. In this case the process operates ina batch mode. The outlet from the fluidic mixer 12 is fed by a pump 7,through a crossflow microfilter 82. The suspension of crystals emergingfrom the microfilter 82 is fed into a batch mixing tank 72 to whichfresh wash liquor is supplied through a duct 73; the spent washingliquor emerges as the filtrate liquid through duct 83. In operation themixing tank 72 may initially be full of fresh wash liquor, and in thefirst stage the crystals gradually flow into the first mixing tank 72,as spent washing liquor emerges from duct 83 (to drain).

As a second stage, flow through the fluidic mixer 12 is stopped (valve75), and instead the suspension in the mixing tank 72 is recirculated bythe pump 74 through the microfilter 82 while continuously supplyingfresh washing liquor into the mixing tank 72 to mainLain the liquidlevel constant. During this second stage the rate of supply of freshwashing liquor through the duct 73 is equal to the rate at whichpermeate liquid (spent washing liquor) emerges from the duct 83. Thiscan be continued until the required degree of purity is achieved. Anydesired additional ingredients can then be added to the suspension inthe mixing tank 72, through the duct 73. The suspension can then bepumped by pump 78 to the spray dryer 40.

It will be appreciated that a crystal preparation apparatus may differfrom those described above while remaining within the scope of thepresent invention. For example in the apparatus 60 of FIG. 5, thesuspension of crystals emerging through the duct 65 from the secondhydrocyclone 64 might first be passed into a batch mixing tank 32 (as inthe apparatus 30) or through a second vortex mixer 52 (as in theapparatus 50) in order to dilute the suspension, prior to spray drying.This would reduce the chance of crystal agglomerates forming in thespray drying process. Furthermore, additional ingredients (whether assmall crystals in suspension, or as a solution) may be added to thecrystal suspension in such a batch mixing tank 32 or vortex mixer 52.

It will also be appreciated that where the process requires the additionof an additional ingredient in the form of small crystals, thesecrystals may be produced in a similar manner to those of the primarymaterial. That is to say they may be produced by mixing a solvent andantisolvent in another ultrasonically irradiated fluidic vortex mixer12, and if necessary they may be subjected to a washing step (e.g. usinghydrocyclones 62 and 64, as in the apparatus 60) before being mixed as asuspension with the suspension of crystals of the primary material. Insuch a context, where the suspensions of crystals of the primarymaterial and the additional ingredient emerging from the respectiveultrasonically irradiated fluidic vortex mixers 12 both need to besubjected to a washing step, instead of operating the washing steps inparallel the outputs from the two fluidic vortex mixers 12 might firstbe mixed together, and then be subjected to a common washing step.

It will also be understood that a crystal preparation apparatus of theinvention may be suitable for use in crystallising a wide variety ofdifferent compounds. Some materials for which such apparatus would beuseful, in order to provide a narrow particle size distribution and soto help control bio-availability, are: analgesics such as codeine;anti-allergens such as sodium cromoglycate; antibiotics such aspenicillin, cephalosporins, streptomycins, or sulphonamides;antihistamines; anti-inflammatories; bronchodilators; or therapeuticproteins and peptides. This list is not intended to be exhaustive, asthe invention is applicable to substantially any crystallisationprocess. Other possible compounds would be amino-alcohols, pectins, andcomplex sugars. Other contexts in which the size distribution and meansize of particles and their morphology are important to the use of thematerial include dyes and pigments such as azo compounds, andphoto-chromatic compounds, and the production of some catalystmaterials.

For example potassium penicillin G may be precipitated from solution inn-butyl acetate using an alkaline anti-solvent such as potassiumhydroxide or potassium acetate solution. A further benefit in this caseis that the intense mixing in the presence of ultrasound inhibits thecreation of localized regions of high-pH, in which the base-catalysedformation of the impurity penicilloic acid may occur. The more uniformsize distribution is desirable in this case, as is the suppression offouling.

As another example, a range of different proteins may be precipitated.For example pectins can be precipitated from an aqueous solution usingan ethanol anti-solvent, and possibly also adjustment of pH. Complexsugars such as glucosamine may also be precipitated. Other sugar-relatedcompounds such d-maltose, sucrose, and d-cellobiose can be crystallisedin a similar way: these compounds dissolve in hot water, but do notreadily crystallise when cooled (a saturated solution at 50° C. will notform crystals even when cooled to 20° C. and left for 24 hours), butform small crystals in the presence of ultrasound.

1. A method for preparing dry crystals from a suspension of crystals insuspension in a liquid, the crystals being of a well-defined size thatis in the range 1 μm to 10 μm, the method being characterised by spraydrying the suspension using an atomiser tuned to create small dropletsin such a way that each droplet should contain not more than onecrystal, the liquid being such that droplets that contain no crystalswill evaporate completely.
 2. A method as claimed in claim 1, alsocomprising treating the suspension so as to add or remove ingredients,or dilute the suspension, prior to the spray-drying step.
 3. A method ofpreparing dry crystals from a saturated solution, in which the saturatedsolution is mixed with an anti-solvent by passage through a fluidicvortex mixer, the liquid within the fluidic vortex mixer being subjectedto high intensity ultrasound to initiate crystallisation and so to forma suspension of crystals of a well-defined size that is in the range 1μm to 10 μm, and characterised by treating the suspension so as to addor remove ingredients, or dilute the suspension, and then spray dryingthe suspension using an atomiser tuned to create small droplets in sucha way that each droplet should contain not more than one crystal, sothat the resulting dry crystals are of a narrow size distribution, andthe liquid in the sprayed suspension being such that droplets thatcontain no crystals will evaporate completely.
 4. A method as claimed inclaim 1 wherein the atomiser is a pneumatic or rotary atomiser.
 5. Amethod as. claimed in claim 1 wherein the droplets are about two orthree times the crystal size.
 6. A method as claimed in claim 5 whereinthe droplets are more than about twice the crystal size, and wherein themethod also comprises diluting the suspension before the spray dryingstep.
 7. A method as claimed in claim 1 involving the step of mixing thesuspension of crystals with other ingredients before the spray dryingstep, wherein the mixing is carried out in a batch mixing tank, or witha fluidic vortex mixer.
 8. A method as claimed in claim 1 involving boththe step of removing solutes from the suspension, and also the step ofmixing the suspension of crystals with other ingredients, before thespray drying step.
 9. A method as claimed in claim 1 involving the stepof removing solutes from the suspension wherein the solutes are removedby causing the suspension to flow in counter current to a wash liquorthrough a series of two or more hydrocyclones.
 10. A method as claimedin claim 1 involving the step of removing solutes from the suspension bycombining the suspension with a wash liquid, and subjecting it tocross-flow filtration using a microfilter or ultrafilter to remove theexcess liquid.
 11. A method for preparing dry crystals from a suspensionof crystals in a liquid, the crystals in suspension being of awell-defined size that is in the range 1 micron to 10 microns, themethod being characterised by spray drying the suspension using anatomiser tuned to create small droplets in such a way that each dropletshould contain not more than one crystal, the diameter of the dropletsbeing about two times the size of the crystals in suspension, and theliquid in the sprayed suspension being such that droplets that containno crystals will evaporate completely.
 12. A method as claimed in claim11 also comprising treating the suspension so as to add or removeingredients, or dilute the suspension, prior to the spray-drying step.13. A method for preparing dry crystals from a suspension of crystals ina liquid, the crystals in suspension being of a well-defined size thatis in the range 1 micron to 10 microns, the method being characterisedby spray drying the suspension using an atomiser tuned to create smalldroplets in such a way that each droplet should contain not more thanone crystal, the diameter of the droplets being more than about twicethe size of the crystals in suspension, and the method also comprisesdiluting the suspension before the spray drying step by addingnon-solvent liquid.
 14. A method as claimed in claim 1 wherein thesuspension of crystals is produced by mixing a saturated solution withan anti-solvent and subjecting the mixture to high-intensity ultrasound.15. A method as claimed in claim 11 wherein the suspension of crystalsis produced by mixing a saturated solution with an anti-solvent andsubjecting the mixture to high-intensity ultrasound.
 16. A method asclaimed in claim 13 wherein the suspension of crystals is produced bymixing a saturated solution with an anti-solvent and subjecting themixture to high-intensity ultrasound.